Human central nervous system (CNS) disorders are heterogeneous diseases that affect a growing number of the population. Over 9.5% of the population in the United States suffers from depressive disorders. Pharmacological studies have shown that alteration of the storage and/or metabolism of neurotransmitters such as serotonin and norepinephrine in the vesicles of presynaptic nerve endings could improve CNS disorders and diseases such as depression, memory or cognitive impairment, anxiety, and other diseases. For example, upon stimulation, nerve cells release serotonin and other neurotransmitters into the synaptic cleft to propagate nerve impulses. Thus, a potential treatment for depression may involve the inhibition of the natural reuptake of serotonin or other neurotransmitters back into the cells. For example, serotonin reuptake inhibition by selective serotonin reuptake inhibitors (SSRIs) result in a progressive increase in extracellular serotonin neurotransmitter concentrations and stimulation of postsynaptic receptors. However, SSRIs have a number of shortcomings including the slow onset of therapeutic action and tolerance and/or recalcitrance of efficacy.
Another target of antidepressant administration is the cAMP signal transduction system, because chronic SSRI antidepressant treatment up-regulates this intracellular cascade at several levels. It has been noted that in animals treated repeatedly with SSRIs, cyclic AMP phosphodiesterase (form 4) (PDE4) is upregulated. Inhibitors of PDE4, such as rolipram, produce both antidepressant-like and memory-enhancing effects in preclinical models. Consistent with this, it has been shown that drugs from this class possess clinical antidepressant efficacy, including reversal of cognitive deficits that occur in depression, as well as memory improvement and cognition enhancement for Alzheimer's Disease.
Current drug development theory suggests that compounds with molecular weight exceeding 500 daltons do not enter the CNS. In addition, the synergistic effects of combining SSRI functional activity and PDE4 inhibitory activity in one molecule has previously not been recognized. For many antidepressants in clinical use today, metabolism of a prodrug moiety is responsible for converting the molecule into a pharmacologically active compound. Thus, it is suggested that imipramine is converted to desimipramine that also possesses significant pharmacological activity. In this way, the drug may attain a more desirable pharmacokinetic or pharmacodynamic profile. It is likely that this is taking place for numerous CNS agents in this class of therapeutics.
Additional agents with pharmacological activity against CNS neurotransmitter receptors and/or intracellular signaling events downstream of neurotransmitter receptor binding are needed. This present invention as described herein meets this and other needs.